Substituted nonanoic acids and process of preparing same



Patented Jan. 16,l 1951 C PATENT O FFICE;

2,538,096 "ffl :ijE NoNANoIo ACIDS! AND PROCESS' oF PREPARING Y zehnmalVanexar-r Falkers; Prailfiela; N. 1.as'-

signoris tof` Mercis & C'o., In'c'., Ralhwy, N'. J., a. corporation of-New Jersey 13 Claims. (Cl. 260404.55"

This` invention is concerred generally` with` It" snow found' that this'compound can be synnove1` chemical compounds and' processes for thesiedLas follows: aceloacet'ic ester, or an alkali preparing the salme;l moreprticulrly, it l'fflllfls"A derivative" thereof; ca fue' reacted in thepresence to novel compounds useful is ihtermediates 4in of anaman-metal' alcohoiate with an omegathe Synthesis 0f 5,11 gmYYthpomotnfacto? 5 halo-caproic ester to produce an a-acetyl suberic d'desbholotfan@ Stfreolhsfmer? met??? ester, which can be decarboxylated uponhydrol- ,dl'qestmqbotm ,15; one of Ph? llxsoners of the ysisto give`8-ketononanoic acid. Thisacid, aft- Chemcl compofmd mm'elqofngahol' acider esterication, can be reacted successively with having the emplrmalformula' CIHISGZNZ and the lo alkyl nitrite to- )produce` 7-ison-itrosc- S-ketostructural' formula? nonanocr esser and: thisA canthen be reacted withK I@ can be prepare-d1 mom wennl` by hyciru'gerwl-J15 thfgbfl 7111.011gffydflyzd"afidcmelted yss with Raney nickel catalystand, has; beam to'the desired 'II'SMurdd noianoic acid bylreacfound, topossess growth promotng activity for tion with phosgene. These reactionsCsm` be irr-K yeasl'i` 1 l dlcated as follows:

` OOR MCH) OOR YOR ('2) CHSCOCHoooR 00H o (l) CHzC z 9 s (CHZMCOORllydrolysis' n N Non omo wel-(onlne o on (5) (/mon @l `miroir-maemomyleoori of Raney nickel catalyst, as` described in copendingapplication Serial No. 509,772, filed Nov. 10, 1943, now Patent No.2,424,311, issued July 22, 1947, and these racemic esters can beconverted to the corresponding free acids by hydrolysis of the7:8diamino-nonanoic esters thus obtained. The hydrogenation of the7:8-dioximino-nonanoic ester or acid can be carried out as disclosed inthis application by reacting said dioximino compound withy hydrogen inthe presence of a mixture comprising an acyl anhydride and a catalystsuch as platinum oxide or Raney nickel, to produce a mixture of theracemates of the 7:8- diacylamido-nonanoic ester or acid. Where theester is obtained, this can be converted to the correspondingdiacylamido-nonanoic acid by heating with aqueous-alcoholic alkalifollowed by acidication.

The present invention is primarily concerned with a method for preparingeach of the stereoisomeric racemates described above in substantiallypure form. This is accomplished by hydrogenclyzing a substantially purestereoisomeric racemate selected from the group which consists ofracemates of compounds having the general formulae:

Roo m130 rlin NH en -(lin Hg-s-Cmcnmooon and Roo Roo 1TH im o cir- GH(10') GHz-s-omonniooon wherein R represents an alkyl, aryl or aralkyl dgroup, in the presence of Ran'ey nickel catalyst to produce thecorresponding racemate of compounds of the formulae:

y Roo Roo NH NH wherein R has the signicance above-defined.

The product obtained, the corresponding racemate of the7:8-(diacylamido)-nonanoic acid'cr ester, can be hydrolyzed by heatingwith an aqueous solution of an alkali metal or alkaline earth metalhydroxide; but it is presently preferred to use aqueous barium hydroxidesolution. The resultant dl-7z8-diamino-nonanoic acid is then convertedto the corresponding 3:4-ureido compound by treatment in alkalinesolution with phosgene.

Inasmuch as the process according to this invention is applicable tocompounds of the general class represented by Formulae 10 and 10 above,

4 it will be apparent that equivalent compounds within this generalclass can be substituted for the specific compounds mentioned in thefollowing examples to obtain the same reaction product. Among theseequivalent starting materials are:

2-(4'carboethoxybutyl) 3 acetamido-i-benzamido-tetrahydrothiophene l f2- (4carbomethoxybutyl) -3-acetamido-4-benzamido-tetrahydrothiophene.

2- (4carbobenzoxybutyl) -3-acetamido-4 benzamido-tetrahydrothiophene.

2-(4carbopropoxybuty1)-3-benzamido 4-acetamido-tetrahydrothiophene.

2-(4carboethoxybutyl) 3 propamido-4-benzamido-tetrahydrothiophene2-(4carbophenoxybutyl) -3-propamido-4-benzamido-tetrahydrothiophene, orthe corresponding acids, the 2(4carboxybutyl) -3:ll-diacylamido-tetrahydrothiophenes As described in the vco-pendingapplications mentioned above-synthesis of 2-(4-carboxy-butyl) :4-(diacylamido) -tetrahydrothiophene esters yields several racemicmixtures of stereoisomers. In the case of 2-(4carbomethoxy butyl) -3acetamido 4 benzamido-tetrahydrothiophene, the isomers obtained are:

(1) The cis-isomer racemate (M. P. 15S-154 C.)

(2) The trans-allo-isorner racemate (M. P.

(3) The trans-epiallo-isomer racemate (M. P.

When these stereoisomeric racemic esters are saponified by heating withaqueous alcoholic alkali followed by acidification of the reactionmixture the corresponding racemic acids are obtained, namely:

benzamido-tetrahydrothiophene (M. P. 232 C.)

(2) d1-Trans-allo-2-(4J-carboxy-butyl) 3-acetamido-l-benzamidotetrahydrothiophene (M. P. 195 C.)

(3) dl-Trans-epiallo 2 (4 carboxy-butyl) -3- acetamido 4benzamido-tetrahydrothiophene (M. P. 190-192 C.)

When these several racemic acids are subjected to the hydrogenolysisoperation, it is found that the cis-isomer racemate yields, according tothis invention, dl-7-acetamido-8-benzamido-nonanoic acid (M. P. 192 C.)whereas both the trans-alloisomer racemate and the trans-epiallo isomerracemate yield dl-allo-7-acetamido-S-benzamidononanoic acid (M. P.169-170 C.). If the racemates of2-(4carbomethoxybutyl)-3-acetamido-/l-benzamido-tetrahydrothiophene arehydrogenolyzed, the corresponding racemates ofmethyl-7-acetamido-8-benzamido-nonanoate are obtained.

The hydrogenolysis operation 'is carried out by arcane@ be understoodthat these examples are. given by CHoo omero Way of illustration and notof limitation.

Example 1 Hydrogen. platinum A solution of about 6 g. ofethyl-'lzedioximinononanoate in about 120 cc of acetic anhydride ishydrogenated at approximately 2 atmospheres pressure using approximately0.3 g. of Adams platinum oxide catalyst. The rate of hydrogen absorptionis such that approximately two-thirds of the theoretical amount isabsorbed at the end of approximately 2 hours, at which time the catalystis filtered oif and. about 0.6 g. of fresh catalyst is added. At the endof an additional hour, the theoretical amount of` hydrogen is absorbed.The catalyst is then filtered off and Washed several times With hotacetic acid and the solution is concentrated to dryness. The solidresidue is dissolved in chloroform and allowed to stand overnight. Theslightly cloudy solution is filtered and again concentrated. Theprecipitate which forms is filtered and washed with ether and dried; toproduce 7:8-diacetamido-nonanoic acid ethyl` ester, (M. 1:'.` H2L-173C.) if the product is recrystallized from benzene, a jell is obtainedwhich upon drying melts at 181-182 C.

Example 2` About 36.5 g. of 'l'-dioximino-nonanoic acid are dissolvedin' a mixture of about '100cc. of glacial' acetic acid and` about 1050cc. of acetic anhydride. This solution is reduced in an atmosphere ofhydrogen at room temperature until 4 moles of hydrogen has been`absorbed, usingf approximately 6 to 9 g. of Raney nickel catalyst. It isimportant to allow the reduction to go to completion; otherwise theproduct is of gummy consistency. The catalyst is removed and the liquoris concentrated to dryness under reduced pressure. The residue isdigested, with ether, allowed to stand overnight in the refrigerator,then ltered, Washed with ether and` dried to produce approximately 29 g.of crude 7:8-diacet.- amido-nonanoic acid which can be puried bytrituratinef withA ethyl acetate.= and'. thenV with chloroform.. i I.EmampZeSf NH' llIH Raneynickel H .a o

About 3.7 g. of dl-trans-allo-Z-(4carboxy butyl) 3` acetamido -4-benzamido-tetral'iydrothiophene (M. P. 195 C.) i's dissolved in' about1110 cc. of 0.5% sodium carbonate solution and' the resulting solutionis heated to approximately '75cy C'. and" treated with about 40 g; ofRan'ey nickel catalyst. The mixture is stirred vigor'- ously for about15I minutes at about 75 C. thel slurry s cooled and the catalyst removedby' centrifuging. The catalyst is then Washed twice with cc. portions of0.5% sodium carbonate solution and once with 150 cc. of Water. Thecombined liquors are neutralized to a pI-I of'about" 7 with sulfuricacid, after which thepre'cipitate of aluminum oxide which.V forms isremoved by ltration through diatomaceous silica. The clear ltrate isacidied further-to apI-I` of aboutf 3 and then concentrated toapproximately @L00 cc. volume. The product which crystallizes is lftered and washed withY water and is recrystallized.V from boiling` waterto produce substantially pure (M. P. 169-170 C.).

Example 4 The procedure of Example 3 is repeated. but dltrans-epiallo-Z-(4'carboxybutyl)i-S-acetamido-4-benzamido-tetrahydrothiophene (M. P. 192 CLl is` substituted for thestarting material therein indicated` After purification bycrystallization from boilingiwater, the productmelts at 16g-170 C.,` andthe.'` mixture of` this compoundwith that obtained fromell-trans-allo-Z-(4'carboxyi-butyl) 3` -acetamido-l-benzamidotetrahydrothiophene in; Example 3:` likewise melts at 169-170" C. The'product is therefore dl-alloJ-acetamido-B-ben.- zamdo-nonanoic acid.

The procedure of Example 3 is repeated but dl-cis-Z-(4'carboXy-butyl-3ac`etamido4 benzamido-tetrahydrothiophene (M. P.ZBO-231 C.) is substituted for the starting material therein employed.After purification, the product, dl-7 acetamido-'lbenzamidononanoioacid.` melts at 192 C.

Example 6 'The dl-allo-'I-acetamido-S-benzamido -nonanoic acid (M. P.16S-170 C.) is obtained as indicated in Examples 3 and 4 by thehydrogenolysis of either the dl-trans-allo isomer racemate or thedl-trans-epiallo isomer racemate of 244- carboxy-butyl)3-acetamido-4-benzarnido-tetrahydrothiophene; about 0.5 g. of thisdiacylamidononanoic acid is hydrolyzed by heating with about 25 g. ofhydrated barium hydroxide dissolved in about 100 cc. of water forapproximately 15 hours at about 140 C. The solution is acidied withsulfuric acid and the barium sulfate removed by filtration. The solutionis then concentrated to dryness to obtain the dlal1o-7:8diamino-nonanoic acid sulfate. This product is then dissolved in anaqueous solution of sodium carbonate, the solution is cooled to about C.and phosgene is passed through the solution until, when tested usingCongo red as an indicator, it shows an acidic reaction. On cooling andstanding, racemic dl-allo-'Z:B-ureido-nonanoic acid crystallizes and isrecovered by filtration and dried; M. P. 164 C. This product isidentical with dl-desthioallobiotin prepared by hydrogenolysis ofdl-allobiotin and dl-epiallobiotin using Raney nickel catalyst accordingto the procedure described in Example 3 above.

Eample 7 The dl-'-acetamido 8 benzamido-nonanoic acid (M. P. 192 C.) isobtained as indicated in Example 5 by the hydrogenolysis of the dl-cisisomer racemate of 2- (4'carboxybutyl)-B-acetamido-4-benzamido-tetrahydrothiophene; about 0.5 g. of thisdiacylamido-nonanoic acid is hydrolyzed by the procedure described inExample 6 to produce dl-7:8diaminononanoic acid sulfate. This product isthen treated with phosgene in the manner described in Example 6 toproduce dl-'ZzS-ureido-non-anoic acid; M. P. 165-166 C. This product isidentical with the dl-desthiobiotin obtained by hydrogenolysis ofdl-biotin; a mixture of this dl-desthiobiotin with thedl-desthioallobiotin obtained in Example 6 meltsV at about 144 C.proving that these two compounds are not the same.

Modifications may be made in carrying out the present invention withoutdeparting from the spirit and scope thereof, and the invention is to belimited only by the appended claims.

We claim:

1. Compounds having the formula:

wherein R and R' are radicals selected from the class which consists ofalkyl, aryl and aralkyl radicals, and R is a radical selected from theclass which consists of hydrogen, alkyl, aryl and aralkyl radicals. Y p

2. dl-'7z8-disubstituted nonanoic acids in which the substituents in the'7- and -positions have the formulae: RCONH- and RCONH- respectively,wherein R and R are radicals selected from the class which consists ofalkyl, aryl and aralkyl radicals.

3. dl-Al1o-7:8-disubstituted nonanoic acids in which the substituents inthe 7- and -positions have the formulae: RCONH- and R'CONH-respectively, wherein R and R are radicals selected from the class whichconsists of alkyl, aryl and aralkyl radicals..

4. Ethyl-7 S-diacetamido-nonanoate.

5. dl-'-acetamido-S-benzamido-nonanoic acid having a melting point ofabout 192 C.

6. dl-Allo -7- acetamido-S-benzamido-nonanoic' acid having a meltingpoint of about 170 C.

7. A process which comprises reacting ethyl- 'lz-dioximino-nonanoatewith hydrogen in the presence of platinum oxide and acetic anhydride toproduce ethyl-'7:S-diacetamido-nonanoate.

8. A process which comprises hydrogenolyzing a compound represented bythe general formula:

wherein R is a radical selected from the group which consists of alkyl,aryl and aralkyl radicals and R' is a radical selected from the groupwhich consists of hydrogen, alkyl, aryl and aralkyl radicals, byreacting said compound with Raney nickel to produce a compound havingthe formula:

9. A process which comprises hydrogenolyzing the stereoisomericracemate, dl-cis-2-(4car boXy-butyl) 3-acetamido-4-benzamido-tetrahydrothiophene, by reacting said racematewith Raney nickel to produce dl-'-acetamido-S-benzamido-nonanoic acid.

10. A process which comprises hydrogenolyzing a stereoisoineric racemateselected from the group which consists of the dl-trans-allo-isomerracemate and the dl-trans-epiallo-isorner racemate of2-(4carboxybutyl)-3 -acetamido-ibenzamido-tetrahydrothiophene, byreacting said racemate with Raney nickel to produce dl-allo-Z-acetamido-B-benzamido-nonanoic acid.

11. The process of preparing racemates of '7:8- ureido-nonanoic acid4which comprises reacting Raney nickel with a stereoisomeric racematehaving the formula:

wherein R and R are radicals selected from the class which consists ofalkyl, aryl and aralkyl radicals, and R" is a radical selected from thegroup which consists of hydrogen, alkyl, aryl and aralkyl radicals,hydrolyzing the compound thus produced and reacting the hydrolyzedproduct with phosgene.

12. The process of preparing dl-desthiobiotin which comprises reactingRaney nickel with dlcis-2- (4carboxy-butyl)-3-acetamido-4-benzamido-tetrahydrothiophene, hydrolyzing the compoundthus produced and reacting the hydrolyzed product with phosgene.

13. The process of preparing dl-desthio-allobiotin which comprisesreacting Raney nickel with a racemate selected from the group whichconsists of dl-trans-allo-Z-(4-carboxybutyl)-3-acetamido-4-benzamido-tetrahydrothiophene and Yd1-trans-epia11o-2-(4-carboxy-butyl) -3-acetam- A l0ido-4-benzamido-tetrahydrothiophene, hydrolyz- OTHER REFERENCES ing thecompound thus produced and reacting the Melville et aL: J. Biol. Chem145 (1942i)1 pn hydrolyzed product with phosgene. 101 5 STANTON A-HARRIS- Hofmann: Advances in Enzymology, vol. 3 ANDREW N- WILSON- 51943), pp. 294-304. KARL FOLKERS 5 Hfmann et a1.: J. Biol. chem., July29, 1941, REFERENCES CITED DI" 205-214' Science, November 20, 1942, vol.96 (1942), pp. The following references are of record in the 455-61, fueof this patent: 10 Vigneaud et a1.; J.Bio1. chem.,vo1.146 (1942 TENT pp.475-85. UNITED STATES PA S Schmidt: Chemistry of Amino Acids and Pro-Nlmbef Name Date zteiriisss, charles Thomas, pp. fio-64.

23741915 Bersworth May 1 1945 Shriner and Fuson: Identification ofOrganic 2,400,288 Caesar et al May 14. 1946 15 Compounds 2nd edition,194()I Wileyl pp 14447.

2,424,311 Harris July 22, 1947 Certificate of Correction Patent No.2,538,096 January 16, 1951 STANTON A. HARRIS ET AL.

It is hereby oerted that error appears in the printed specification ofthe above numbered patent requrmg correction as follows:

Columns 1 and 2, formula (6) for Non Non Non Non oHa--o (oHmo o o R readOmit- (CHmG o 0R column 11, line 22, for ZH-carboxy read 2(J/earb0y;column 8, line 30,

following the second formula, insert wherein R and R have the sgm'yeaneeabo/ve defi/ned.;

and that the said Letters Patent should be read as corrected above, sothat the same may conform to the record of the ease in the PatentOflice.

Signed and. sealed this 10th day of April, A. D. 1951.

[SEAL] THOMAS F. MURPHY,

Assistant Uommz'ssz'oner of Patents.

1. COMPOUNDS HAVING THE FORMULA: 